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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2589.)
© 2007 American Heart Association, Inc.

Vascular Biology

Aortic Msx2-Wnt Calcification Cascade Is Regulated by TNF-–Dependent Signals in Diabetic Ldlr^–/– Mice

Ziyad Al-Aly; Jian-Su Shao; Chung-Fang Lai; Emily Huang; Jun Cai; Abraham Behrmann; Su-Li Cheng; Dwight A. Towler

From the Department of Medicine (Z.A.-A.), Division of Nephrology, St. Louis VA Medical Center, St. Louis University, and the Department of Medicine (J.-S.S., C.-F.L., E.H., J.C., A.B., S.-L.,C., D.A.T.), Center for Cardiovascular Research, Division of Bone & Mineral Diseases, Washington University, St. Louis, Mo.

Correspondence to Dwight A. Towler, MD, PhD, Division of Bone and Mineral Diseases, Washington University School of Medicine, Campus Box 8301, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail dtowler{at}im.wustl.edu

Objective— Aortic calcification is prevalent in type II diabetes (T2DM), enhancing morbidity and tracking metabolic syndrome parameters. Ldlr^–/– mice fed high-fat "Westernized" diets (HFD) accumulate aortic calcium primarily in the tunica media, mediated via osteogenic morphogens and transcriptional programs that induce aortic alkaline phosphatase (ALP). Because elevated TNF- is characteristic of obesity with T2DM, we examined contributions of this inflammatory cytokine.

Methods and Results— HFD promoted obesity, hyperglycemia, and hyperlipidemia, and upregulated serum TNF- in Ldlr^–/– mice. Serum haptoglobin (inflammatory marker) was increased along with aortic expression of BMP2, Msx2, Wnt3a, and Wnt7a. Dosing with the TNF- neutralizing antibody infliximab did not reduce obesity, hypercholesterolemia, or hyperglycemia; however, haptoglobin, aortic BMP2, Msx2, Wnt3a, and Wnt7a and aortic calcium accumulation were downregulated by infliximab. Mice with vascular TNF- augmented by a transgene (SM22-TNFTg) driven from the SM22 promoter upregulated aortic Msx2, Wnt3a, and Wnt7a. Furthermore, SM22-TNFTg;TOPGAL mice exhibited greater aortic β-galactosidase reporter staining versus TOPGAL sibs, indicating enhanced mural Wnt signaling. In aortic myofibroblast cultures, TNF- upregulated Msx2, Wnt3a, Wnt7a, and ALP. ALP induction was inhibited by Dkk1, an antagonist of paracrine Wnt actions.

Conclusions— TNF- promote aortic Msx2-Wnt programs that contribute to aortic calcium accumulation in T2DM.

Type II diabetes (T2DM) promotes medial artery calcification, a significant risk factor for lower extremity amputation. Using a murine disease model—the Ldlr^–/– mouse fed high fat diabetogenic diets—we identified that arterial TNF-alpha signaling activates osteogenic Msx2-Wnt gene expression programs that direct medial calcification during disease initiation.

Key Words: aortic calcification • Wnt • TNF- • metabolic syndrome • diabetes

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